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1.  Modulation of Neurotransmission by GPCRs Is Dependent upon the Microarchitecture of the Primed Vesicle Complex 
The Journal of Neuroscience  2014;34(1):260-274.
Gi/o-protein-coupled receptors (GPCRs) ubiquitously inhibit neurotransmission, principally via Gβγ, which acts via a number of possible effectors. GPCR effector specificity has traditionally been attributed to Gα, based on Gα's preferential effector targeting in vitro compared with Gβγ's promiscuous targeting of various effectors. In synapses, however, Gβγ clearly targets unique effectors in a receptor-dependent way to modulate synaptic transmission. It remains unknown whether Gβγ specificity in vivo is due to specific Gβγ isoform-receptor associations or to spatial separation of distinct Gβγ pathways through macromolecular interactions. We thus sought to determine how Gβγ signaling pathways within axons remain distinct from one another. In rat hippocampal CA1 axons, GABAB receptors (GABABRs) inhibit presynaptic Ca2+ entry, and we have now demonstrated that 5-HT1B receptors (5-HT1BRs) liberate Gβγ to interact with SNARE complex C terminals with no effect on Ca2+ entry. Both GABABRs and 5-HT1BRs inhibit Ca2+-evoked neurotransmitter release, but 5-HT1BRs have no effect on Sr2+-evoked release. Sr2+, unlike Ca2+, does not cause synaptotagmin to compete with Gβγ binding to SNARE complexes. 5-HT1BRs also fail to inhibit release following cleavage of the C terminus of the SNARE complex protein SNAP-25 with botulinum A toxin. Thus, GABABRs and 5-HT1BRs both localize to presynaptic terminals, but target distinct effectors. We demonstrate that disruption of SNARE complexes and vesicle priming with botulinum C toxin eliminates this selectivity, allowing 5-HT1BR inhibition of Ca2+ entry. We conclude that receptor-effector specificity requires a microarchitecture provided by the SNARE complex during vesicle priming.
PMCID: PMC3866488  PMID: 24381287
2.  Role of presynaptic metabotropic glutamate receptors in the induction of long-term synaptic plasticity of vesicular release 
Neuropharmacology  2012;66:31-39.
While postsynaptic ionotropic and metabotropic glutamate receptors have received the lions share of attention in studies of long-term activity-dependent synaptic plasticity, it is becoming clear that presynaptic metabotropic glutamate receptors play critical roles in both short-term and long-term plasticity of vesicular transmitter release, and that they act both at the level of voltage-dependent calcium channels and directly on proteins of the vesicular release machinery. Activation of G protein-coupled receptors can transiently inhibit vesicular release through the release of Gβγ which binds to both voltage-dependent calcium channels to reduce calcium influx, and directly to the C-terminus region of the SNARE protein SNAP-25. Our recent work has revealed that the binding of Gβγ to SNAP-25 is necessary, but not sufficient, to elicit long-term depression (LTD) of vesicular glutamate release, and that the concomitant release of Gαi and the second messenger nitric oxide are also necessary steps in the presynaptic LTD cascade. Here, we review the current state of knowledge of the molecular steps mediating short-term and long-term plasticity of vesicular release at glutamatergic synapses, and the many gaps that remain to be addressed.
PMCID: PMC3432151  PMID: 22626985
Group II metabotropic glutamate receptors; G protein-coupled receptors; Giα; Gβγ; long-term synaptic depression; SNAP-25; SNARE protein; synaptic plasticity; vesicular release
3.  A synaptic mechanism for network synchrony 
Within neural networks, synchronization of activity is dependent upon the synaptic connectivity of embedded microcircuits and the intrinsic membrane properties of their constituent neurons. Synaptic integration, dendritic Ca2+ signaling, and non-linear interactions are crucial cellular attributes that dictate single neuron computation, but their roles promoting synchrony and the generation of network oscillations are not well understood, especially within the context of a defined behavior. In this regard, the lamprey spinal central pattern generator (CPG) stands out as a well-characterized, conserved vertebrate model of a neural network (Smith et al., 2013a), which produces synchronized oscillations in which neural elements from the systems to cellular level that control rhythmic locomotion have been determined. We review the current evidence for the synaptic basis of oscillation generation with a particular emphasis on the linkage between synaptic communication and its cellular coupling to membrane processes that control oscillatory behavior of neurons within the locomotor network. We seek to relate dendritic function found in many vertebrate systems to the accessible lamprey central nervous system in which the relationship between neural network activity and behavior is well understood. This enables us to address how Ca2+ signaling in spinal neuron dendrites orchestrate oscillations that drive network behavior.
PMCID: PMC4166887  PMID: 25278839
lamprey; oscillation; SK2; KCa2; NMDA; locomotion; calcium; dendrites
4.  Spotlight on the active zone 
Cellular Logistics  2011;1(3):84-85.
PMCID: PMC3173654  PMID: 21922071
5.  A parallel cholinergic brainstem pathway for enhancing locomotor drive 
Nature neuroscience  2010;13(6):731-738.
The brainstem locomotor system is believed to be organized serially from the mesencephalic locomotor region (MLR) to reticulospinal neurons, which in turn, project to locomotor neurons in the spinal cord. In contrast, we now identify in lampreys, brainstem muscarinoceptive neurons receiving parallel inputs from the MLR and projecting back to reticulospinal cells to amplify and extend durations of locomotor output. These cells respond to muscarine with extended periods of excitation, receive direct muscarinic excitation from the MLR, and project glutamatergic excitation to reticulospinal neurons. Targeted block of muscarine receptors over these neurons profoundly reduces MLR-induced excitation of reticulospinal neurons and markedly slows MLR-evoked locomotion. Their presence forces us to rethink the organization of supraspinal locomotor control, to include a sustained feedforward loop that boosts locomotor output.
PMCID: PMC2881475  PMID: 20473293
6.  New Perspectives on the Dialogue between Brains and Machines 
Brain-machine interfaces (BMIs) are mostly investigated as a means to provide paralyzed people with new communication channels with the external world. However, the communication between brain and artificial devices also offers a unique opportunity to study the dynamical properties of neural systems. This review focuses on bidirectional interfaces, which operate in two ways by translating neural signals into input commands for the device and the output of the device into neural stimuli. We discuss how bidirectional BMIs help investigating neural information processing and how neural dynamics may participate in the control of external devices. In this respect, a bidirectional BMI can be regarded as a fancy combination of neural recording and stimulation apparatus, connected via an artificial body. The artificial body can be designed in virtually infinite ways in order to observe different aspects of neural dynamics and to approximate desired control policies.
PMCID: PMC2920523  PMID: 20589094
brain-machine interface; dynamical system; dynamical dimension; neural plasticity; lamprey
7.  Presynaptic G protein-coupled receptors dynamically modify vesicle fusion, synaptic cleft glutamate concentrations and motor behavior 
Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviours, we have investigated effects of presynaptic G protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a Gβγ interaction with the SNARE complex that promotes kiss-and-run vesicle fusion. In the lamprey spinal cord we demonstrate that while presynaptic 5-HT receptors inhibit evoked neurotransmitter release from reticulospinal command neurons, their activation does not abolish locomotion, but rather modulates locomotor rhythms. Liberation of presynaptic Gβγ causes substantial inhibition of AMPA receptor-mediated synaptic responses, but leaves NMDA receptor-mediated components of neurotransmission largely intact. Because Gβγ binding to the SNARE complex is displaced by Ca2+-synaptotagmin binding, 5-HT-mediated inhibition displays Ca2+ sensitivity. We show that as Ca2+ accumulates presynaptically during physiological bouts of activity, 5-HT/Gβγ-mediated presynaptic inhibition is relieved leading to a frequency-dependent increase in synaptic concentrations of glutamate. This frequency dependent phenomenon mirrors a shift in the vesicle fusion mode and a recovery of AMPA receptor-mediated EPSCs from inhibition without a modification of NMDA receptor EPSCs. We conclude that activation of presynaptic 5-HT GPCRs state-dependently alters vesicle fusion properties to shift the weight of NMDA vs AMPA receptor-mediated responses at excitatory synapses. We have therefore identified a novel mechanism in which modification of vesicle fusion modes may profoundly alter locomotor behaviour.
PMCID: PMC2756137  PMID: 19692597
fictive locomotion; kiss-and-run; G protein-coupled receptors; serotonin; presynaptic; Gβγ
8.  Brain-Machine Interactions for Assessing the Dynamics of Neural Systems 
A critical advance for brain–machine interfaces is the establishment of bi-directional communications between the nervous system and external devices. However, the signals generated by a population of neurons are expected to depend in a complex way upon poorly understood neural dynamics. We report a new technique for the identification of the dynamics of a neural population engaged in a bi-directional interaction with an external device. We placed in vitro preparations from the lamprey brainstem in a closed-loop interaction with simulated dynamical devices having different numbers of degrees of freedom. We used the observed behaviors of this composite system to assess how many independent parameters − or state variables − determine at each instant the output of the neural system. This information, known as the dynamical dimension of a system, allows predicting future behaviors based on the present state and the future inputs. A relevant novelty in this approach is the possibility to assess a computational property – the dynamical dimension of a neuronal population – through a simple experimental technique based on the bi-directional interaction with simulated dynamical devices. We present a set of results that demonstrate the possibility of obtaining stable and reliable measures of the dynamical dimension of a neural preparation.
PMCID: PMC2679156  PMID: 19430593
lamprey brainstem; closed-loop system; dynamical dimension; simulated dynamical device

Results 1-8 (8)